IL17RD: Difference between revisions

IL17RD
Identifiers
Aliases	IL17RD, HH18, IL-17RD, IL17RLM, SEF, interleukin 17 receptor D
External IDs	OMIM: 606807; MGI: 2159727; HomoloGene: 9717; GeneCards: IL17RD; OMA:IL17RD - orthologs
Gene location (Human)
Chr.	Chromosome 3 (human)
End	57,170,306 bp
Gene location (Mouse)
Chr.	Chromosome 14 (mouse)
End	26,829,243 bp
RNA expression pattern
	Top expressed in
	secondary oocyte; ; lactiferous duct; ; ganglionic eminence; ; corpus epididymis; ; parietal pleura; ; germinal epithelium; ; sperm; ; endothelial cell; ; saphenous vein; ; myometrium;
	Top expressed in
	primitive streak; ; Bowman's capsule; ; secondary oocyte; ; maxillary prominence; ; ciliary body; ; trigeminal ganglion; ; aortic valve; ; abdominal wall; ; retinal pigment epithelium; ; iris;
	More reference expression data
	n/a
Gene ontology
Molecular function	interleukin-17 receptor activity;
Cellular component	cytoplasm; integral component of membrane; Golgi apparatus; membrane; Golgi membrane; plasma membrane; integral component of plasma membrane; nucleoplasm;
Biological process	MAPK cascade; cytokine-mediated signaling pathway;
	Sources:Amigo / QuickGO
Orthologs
	54756
	171463
	ENSG00000144730
	ENSMUSG00000040717
	Q8NFM7
	Q8JZL1
	NM_017563; NM_001318864
	NM_027265; NM_134437
	NP_001305793; NP_060033
	NP_602319
	Wikidata
View/Edit Human	View/Edit Mouse

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Revision as of 06:46, 21 June 2023

Interleukin 17 receptor D (also known as Sef) is a protein that in humans is encoded by the IL17RD gene.^[1]

This gene encodes a membrane protein belonging to the interleukin-17 receptor (IL-17R) protein family. Alternate splicing generates multiple transcript variants encoding distinct isoforms. IL-17RD has been described to limit fibroblast growth factor receptor (FGFR) signaling and to be a part of the IL-17 receptor signaling complex.

Identification

IL-17RD was initially discovered during a large-scale in situ hybridization screen for genes regulating zebrafish embryogenesis. It was identified as a part of a synexpression group (genes with similar spatio-temporal expression) with negative regulators of fibroblast growth factor (FGF) and termed Sef (similar expression to FGF genes). The name was later changed to IL-17RD due to its sequence similarity to other IL-17 receptors. It was further determined that IL-17RD co-immunoprecipitates with FGF receptor (FGFR) and inhibits FGF signaling at the level of signal transduction and not by interfering with the ligand or its binding to FGFR ^[6]^[7].

Structure

IL-17RD is a type I transmembrane protein containing extracellular Ig-like domain followed by a fibronectin type III domain, a short transmembrane domain of ~20 amino acids, and an intracellular SEFIR domain which was identified in IL-17 receptors and some soluble factors involved in IL-17 signaling ^[8]^[9].

IL-17RD in development

IL-17RD (Sef) was identified as part of a group of genes involved in FGF signaling in zebrafish and Xenopus laevis embryo. Injection of 1-cell stage embryo with sef mRNA lead to ventralization of the embryo, a similar effect observed after injection with XFD (a dominant negative of FGF receptor), suggesting its function as a negative regulator of FGF receptor signaling. Co-immunoprecipitation assay revealed that the intracellular part, but not the SEFIR domain, is critical for IL-17RD association with FGFR ^[6]. One of the pathways activated by stimulation of FGFR is Ras/MAPK (the rest being PI3/AKT and PLCγ). Injection of embryos with high amounts of Ras, Raf or MEK causes cell cycle arrest, which can be rescued by co-injection of IL-17RD, further supporting the role of IL-17RD in negative regulation of FGFR signaling. Moreover, IL-17RD appears to regulate FGF signaling at the level of downstream signaling, not the receptor, since overexpression of FGF or FGFR does not cause cell cycle arrest ^[7]. Taken together IL-17RD seems to negatively regulate FGFR signaling by limiting MAPK signaling via its intracellular domain.

IL-17RD in inflammation

IL-17 signaling

The IL-17 receptor family belongs to a group of structurally similar receptors with a distinctive SEFIR (Sef and IL-17R) domain ^[9]. The founding member, IL-17RA, along with IL-17RC serve as a receptor complex for IL-17. IL-17 is a proinflammatory cytokine mainly produced by Th17 subset of T cells and plays an important role in extracellular pathogen elimination as well as several autoinflammatory diseases (such as psoriasis or rheumatoid arthritis) ^[10]. IL-17RD has been reported to associate and co-localize with IL-17RA, mediate IL-17 signaling, and interact with TRAF6 (an IL-17 downstream molecule). Moreover, deletion of IL-17RD intracellular domain has a dominant negative effect and suppresses IL-17 signaling. In contrast, deletion of extracellular domain had no effect on IL-17 signaling ^[11]. However, full-body IL-17RD knockout mice do not present with any apparent phenotype ^[12]. This might be accounted for by the presence of IL-17RC which to an extent substitutes IL-17RD. It is important to note, however, that IL-17RC or IL-17RD deletion fails to protect against imiquimod-induced psoriasis ^[13].

References

^ "Entrez Gene: Interleukin 17 receptor D". Retrieved 2016-04-17.
^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000144730 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000040717 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ ^a ^b Tsang, Michael; Friesel, Robert; Kudoh, Tetsuhiro; Dawid, Igor B (2002-02). "Identification of Sef, a novel modulator of FGF signalling". Nature Cell Biology. 4 (2): 165–169. doi:10.1038/ncb749. ISSN 1465-7392. {{cite journal}}: Check date values in: |date= (help)
^ ^a ^b Fürthauer, Maximilian; Lin, Wei; Ang, Siew-Lan; Thisse, Bernard; Thisse, Christine (2002-02). "Sef is a feedback-induced antagonist of Ras/MAPK-mediated FGF signalling". Nature Cell Biology. 4 (2): 170–174. doi:10.1038/ncb750. ISSN 1465-7392. {{cite journal}}: Check date values in: |date= (help)
^ Pande, Shivangi; Yang, Xuehui; Friesel, Robert (2021-12). "Interleukin-17 receptor D (Sef) is a multi-functional regulator of cell signaling". Cell Communication and Signaling. 19 (1). doi:10.1186/s12964-020-00695-7. ISSN 1478-811X. PMC 7805053. PMID 33436016. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
^ ^a ^b Novatchkova, Maria; Leibbrandt, Andreas; Werzowa, Johannes; Neubüser, Annette; Eisenhaber, Frank (2003-05). "The STIR-domain superfamily in signal transduction, development and immunity". Trends in Biochemical Sciences. 28 (5): 226–229. doi:10.1016/S0968-0004(03)00067-7. {{cite journal}}: Check date values in: |date= (help)
^ Veldhoen, Marc; Hocking, Richard J.; Atkins, Christopher J.; Locksley, Richard M.; Stockinger, Brigitta (2006-02). "TGFβ in the Context of an Inflammatory Cytokine Milieu Supports De Novo Differentiation of IL-17-Producing T Cells". Immunity. 24 (2): 179–189. doi:10.1016/j.immuni.2006.01.001. {{cite journal}}: Check date values in: |date= (help)
^ Rong, Zhili; Wang, Anan; Li, Zhiyong; Ren, Yongming; Cheng, Long; Li, Yinghua; Wang, Yinyin; Ren, Fangli; Zhang, Xiaoning; Hu, Jim; Chang, Zhijie (2009-02). "IL-17RD (Sef or IL-17RLM) interacts with IL-17 receptor and mediates IL-17 signaling". Cell Research. 19 (2): 208–215. doi:10.1038/cr.2008.320. ISSN 1001-0602. PMC 4603938. PMID 19079364. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
^ Gaffen, Sarah L. (2009-08). "Structure and signalling in the IL-17 receptor family". Nature Reviews Immunology. 9 (8): 556–567. doi:10.1038/nri2586. ISSN 1474-1733. PMC 2821718. PMID 19575028. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
^ Su, Yang; Huang, Jinling; Zhao, Xiaohong; Lu, Huiping; Wang, Wang; Yang, Xuexian O.; Shi, Yuling; Wang, Xiaohu; Lai, Yuping; Dong, Chen (2019-06-07). "Interleukin-17 receptor D constitutes an alternative receptor for interleukin-17A important in psoriasis-like skin inflammation". Science Immunology. 4 (36). doi:10.1126/sciimmunol.aau9657. ISSN 2470-9468.

@@ Line 1: / Line 1: @@
 {{Short description|Protein-coding gene in the species Homo sapiens}}
+'''Interleukin 17 receptor D''' (also known as Sef) is a [[protein]] that in humans is encoded by the IL17RD [[gene]].<ref name="entrez">
-{{Infobox_gene|geneid}}
-'''Interleukin 17 receptor D''' is a [[protein]] that in humans is encoded by the IL17RD [[gene]].
-<ref name="entrez">
 {{cite web
 | title = Entrez Gene: Interleukin 17 receptor D
 | url = https://www.ncbi.nlm.nih.gov/gene/54756
 | access-date = 2016-04-17
-}}</ref>
+}}</ref>{{Infobox_gene|geneid}}
+This gene encodes a membrane protein belonging to the interleukin-17 receptor (IL-17R) protein family. Alternate splicing generates multiple transcript variants encoding distinct isoforms. IL-17RD has been described to limit fibroblast growth factor receptor ([[FGFR]]) signaling and to be a part of the [[Interleukin-17 receptor|IL-17 receptor signaling complex]].
+== Identification ==
+IL-17RD was initially discovered during a large-scale ''in situ'' hybridization screen for genes regulating zebrafish embryogenesis. It was identified as a part of a synexpression group (genes with similar spatio-temporal expression) with negative regulators of fibroblast growth factor ([[Fibroblast growth factor|FGF]]) and termed Sef (similar expression to FGF genes). The name was later changed to IL-17RD due to its sequence similarity to other IL-17 receptors. It was further determined that IL-17RD co-immunoprecipitates with FGF receptor (FGFR) and inhibits FGF signaling at the level of signal transduction and not by interfering with the ligand or its binding to FGFR <ref name=":0">{{Cite journal |last=Tsang |first=Michael |last2=Friesel |first2=Robert |last3=Kudoh |first3=Tetsuhiro |last4=Dawid |first4=Igor B |date=2002-02 |title=Identification of Sef, a novel modulator of FGF signalling |url=https://www.nature.com/articles/ncb749 |journal=Nature Cell Biology |language=en |volume=4 |issue=2 |pages=165–169 |doi=10.1038/ncb749 |issn=1465-7392}}</ref><ref name=":1">{{Cite journal |last=Fürthauer |first=Maximilian |last2=Lin |first2=Wei |last3=Ang |first3=Siew-Lan |last4=Thisse |first4=Bernard |last5=Thisse |first5=Christine |date=2002-02 |title=Sef is a feedback-induced antagonist of Ras/MAPK-mediated FGF signalling |url=https://www.nature.com/articles/ncb750 |journal=Nature Cell Biology |language=en |volume=4 |issue=2 |pages=170–174 |doi=10.1038/ncb750 |issn=1465-7392}}</ref>.
+== Structure ==
+IL-17RD is a type I transmembrane protein containing extracellular Ig-like domain followed by a fibronectin type III domain, a short transmembrane domain of ~20 amino acids, and an intracellular SEFIR domain  which was identified in IL-17 receptors and some soluble factors involved in IL-17 signaling <ref>{{Cite journal |last=Pande |first=Shivangi |last2=Yang |first2=Xuehui |last3=Friesel |first3=Robert |date=2021-12 |title=Interleukin-17 receptor D (Sef) is a multi-functional regulator of cell signaling |url=https://biosignaling.biomedcentral.com/articles/10.1186/s12964-020-00695-7 |journal=Cell Communication and Signaling |language=en |volume=19 |issue=1 |doi=10.1186/s12964-020-00695-7 |issn=1478-811X |pmc=PMC7805053 |pmid=33436016}}</ref><ref name=":2">{{Cite journal |last=Novatchkova |first=Maria |last2=Leibbrandt |first2=Andreas |last3=Werzowa |first3=Johannes |last4=Neubüser |first4=Annette |last5=Eisenhaber |first5=Frank |date=2003-05 |title=The STIR-domain superfamily in signal transduction, development and immunity |url=https://linkinghub.elsevier.com/retrieve/pii/S0968000403000677 |journal=Trends in Biochemical Sciences |language=en |volume=28 |issue=5 |pages=226–229 |doi=10.1016/S0968-0004(03)00067-7}}</ref>.
+== IL-17RD in development ==
+IL-17RD (Sef) was identified as part of a group of genes involved in FGF signaling in zebrafish and ''Xenopus laevis'' embryo. Injection of 1-cell stage embryo with ''sef'' mRNA lead to ventralization of the embryo, a similar effect observed after injection with XFD (a dominant negative of FGF receptor), suggesting its function as a negative regulator of FGF receptor signaling. Co-immunoprecipitation assay revealed that the intracellular part, but not the SEFIR domain, is critical for IL-17RD association with FGFR <ref name=":0" />. One of the pathways activated by stimulation of FGFR is Ras/MAPK (the rest being PI3/AKT and PLCγ). Injection of embryos with high amounts of Ras, Raf or MEK causes cell cycle arrest, which can be rescued by co-injection of IL-17RD, further supporting the role of IL-17RD in negative regulation of FGFR signaling. Moreover, IL-17RD appears to regulate FGF signaling at the level of downstream signaling, not the receptor, since overexpression of FGF or FGFR does not cause cell cycle arrest <ref name=":1" />. Taken together IL-17RD seems to negatively regulate FGFR signaling by limiting MAPK signaling via its intracellular domain.
+== IL-17RD in inflammation ==
-==Function==
+=== IL-17 signaling ===
-This gene encodes a membrane protein belonging to the interleukin-17 receptor (IL-17R) protein family. The encoded protein is a component of the [[interleukin-17 receptor signaling complex]], and the interaction between this protein and IL-17R does not require the interleukin. The gene product also affects [[fibroblast growth factor]] signaling, inhibiting or stimulating growth through MAPK/ERK signaling. Alternate splicing generates multiple transcript variants encoding distinct isoforms.
+The IL-17 receptor family belongs to a group of structurally similar receptors with a distinctive SEFIR (Sef and IL-17R) domain <ref name=":2" />. The founding member, IL-17RA, along with IL-17RC serve as a receptor complex for IL-17. IL-17 is a proinflammatory cytokine mainly produced by Th17 subset of T cells and plays an important role in extracellular pathogen elimination as well as several autoinflammatory diseases (such as psoriasis or rheumatoid arthritis) <ref>{{Cite journal |last=Veldhoen |first=Marc |last2=Hocking |first2=Richard J. |last3=Atkins |first3=Christopher J. |last4=Locksley |first4=Richard M. |last5=Stockinger |first5=Brigitta |date=2006-02 |title=TGFβ in the Context of an Inflammatory Cytokine Milieu Supports De Novo Differentiation of IL-17-Producing T Cells |url=https://linkinghub.elsevier.com/retrieve/pii/S1074761306000045 |journal=Immunity |language=en |volume=24 |issue=2 |pages=179–189 |doi=10.1016/j.immuni.2006.01.001}}</ref>. IL-17RD has been reported to associate and co-localize with IL-17RA, mediate IL-17 signaling, and interact with TRAF6 (an IL-17 downstream molecule). Moreover, deletion of IL-17RD intracellular domain has a dominant negative effect and suppresses IL-17 signaling. In contrast, deletion of extracellular domain had no effect on IL-17 signaling <ref>{{Cite journal |last=Rong |first=Zhili |last2=Wang |first2=Anan |last3=Li |first3=Zhiyong |last4=Ren |first4=Yongming |last5=Cheng |first5=Long |last6=Li |first6=Yinghua |last7=Wang |first7=Yinyin |last8=Ren |first8=Fangli |last9=Zhang |first9=Xiaoning |last10=Hu |first10=Jim |last11=Chang |first11=Zhijie |date=2009-02 |title=IL-17RD (Sef or IL-17RLM) interacts with IL-17 receptor and mediates IL-17 signaling |url=https://www.nature.com/articles/cr2008320 |journal=Cell Research |language=en |volume=19 |issue=2 |pages=208–215 |doi=10.1038/cr.2008.320 |issn=1001-0602 |pmc=PMC4603938 |pmid=19079364}}</ref>. However, full-body IL-17RD knockout mice do not present with any apparent phenotype <ref>{{Cite journal |last=Gaffen |first=Sarah L. |date=2009-08 |title=Structure and signalling in the IL-17 receptor family |url=https://www.nature.com/articles/nri2586 |journal=Nature Reviews Immunology |language=en |volume=9 |issue=8 |pages=556–567 |doi=10.1038/nri2586 |issn=1474-1733 |pmc=PMC2821718 |pmid=19575028}}</ref>. This might be accounted for by the presence of IL-17RC which to an extent substitutes IL-17RD. It is important to note, however, that IL-17RC or IL-17RD deletion fails to protect against imiquimod-induced psoriasis <ref>{{Cite journal |last=Su |first=Yang |last2=Huang |first2=Jinling |last3=Zhao |first3=Xiaohong |last4=Lu |first4=Huiping |last5=Wang |first5=Wang |last6=Yang |first6=Xuexian O. |last7=Shi |first7=Yuling |last8=Wang |first8=Xiaohu |last9=Lai |first9=Yuping |last10=Dong |first10=Chen |date=2019-06-07 |title=Interleukin-17 receptor D constitutes an alternative receptor for interleukin-17A important in psoriasis-like skin inflammation |url=https://www.science.org/doi/10.1126/sciimmunol.aau9657 |journal=Science Immunology |language=en |volume=4 |issue=36 |doi=10.1126/sciimmunol.aau9657 |issn=2470-9468}}</ref>.
 == References ==